Liver's Role in Cancer Cachexia Uncovered Through Systemic Signaling

Recent research has unveiled a critical role of the liver in the development of cachexia, a syndrome characterized by severe muscle and fat loss in cancer patients. This condition impacts approximately 50% of individuals diagnosed with cancer and is a significant contributor to treatment resistance, complications, and heightened mortality rates.

A collaborative study conducted by Helmholtz Munich, Heidelberg University Hospital, the Technical University of Munich, and the German Center for Diabetes Research has identified the liver as an active participant in cachexia, responding to tumors located in other organs like the pancreas and intestine. The findings, published in the journal Cell, suggest that the liver plays a pivotal role by releasing specific signaling molecules that exacerbate tissue wasting.

In the context of cachexia, researchers observed a fundamental disruption in liver metabolism, particularly involving a gene known for regulating the liver's daily activity. Utilizing a mouse model, they found that this gene, referred to as REV-ERB?, was largely inactive in the context of the disease. Reactivating this gene in the affected mice resulted in a notable reduction in body mass loss.

The research team discovered that REV-ERB? is responsible for regulating several genes that contribute to the production of liver-derived signaling molecules. When this gene is inactive, the liver releases higher levels of factors that promote disease progression. Specifically, three hepatokines--LBP, ITIH3, and IGFBP1--were identified as central to the mechanism that drives cachexia, as they induced catabolic processes in muscle and fat cells, leading to the physical deterioration associated with the syndrome.

Furthermore, elevated levels of these proteins were detected in the blood of cancer patients suffering from cachexia. In preclinical experiments, targeting and inhibiting these factors effectively mitigated their detrimental effects.

Researchers emphasized that this study marks the first time the liver has been recognized as an active contributor to the progression of cachexia, rather than merely a passive responder. This insight opens new avenues for diagnosing the syndrome and exploring potential therapeutic interventions.

The comprehensive dataset generated from this research, detailing the liver's role in cachexia--from molecular interactions to cell type-specific changes--will be made accessible to the scientific community, facilitating further studies beyond the current model.

In the long run, the identified hepatokines may serve as biomarkers for assessing the risk of cachexia or as targets for developing new therapies. With no approved treatments currently available for cachexia, the need for innovative approaches is urgent, highlighting the importance of understanding systemic organ interactions in cancer progression.